I am an Assistant Professor specialized in perinatal pathology at Brown University. Currently I am in a scientifically productive environment which will foster my career development. My research interest is placental implantation. Since Fetal Alcohol Syndrome (FAS) increases the risk of spontaneous abortion and intrauterine growth restriction (IUGR), each of which is related to impaired implantation, FAS serves as a perfect model to study implantation process. Although FAS is the most common preventable cause of birth defects in North America, little is known about the effects of ethanol exposure on placental implantation. Our lab had previously demonstrated the inhibitory role of ethanol on insulin and insulin like growth factor (IGF) signaling. IGF-II promotes fetal and placental growth and stimulates trophoblastic cell motility which mediates implantation. In preliminary studies, we demonstrated that ethanol exposure impairs signaling and function of trophoblastic cells and reduces expression of aspartyl-asparaginyl-beta-hydroxylase (AAH). AAH has a critical role in cell motility and adhesion and regulated by IGF-II"IGF-I stimulation. Since cell motility and adhesion are critical for placental implantation, we hypothesize that gestational exposure to ethanol contributes to FAS phenotype by inhibiting IGF-II mediated AAH expression. The resulting impairments in placental implantation and placental growth cause IUGR and increased frequency of fetal demise. The proposed research plan will utilize established in vitro and in vivo ethanol exposure models and adress 4 specific aims: 1) determine the degree to which different ethanol doses impair placental implantation and AAH expression 2) characterize the effects of ethanol on IGF-II stimulated signaling in relation to AAH expression and motility in HTR/svneod human trophoblastic cells 3) determine the mechanisms by which ethanol inhibits IGF-II stimulated signaling in relation to AAH expression and motility in HTR8/svneo cells 4) chacterize mechanisms by which ethanol perturbs IGF-II stimulated signaling of AAH expression, AAH enzymatic activity, and trophoblastic cell motility/invasion. The proposed studies will lead to a better understanding of the mechanisms underlying IUGR in FAS. This 5-year mentored application will enable me to gain experience in molecular research and data analysis. Through the course of this work, I will progress to independence and prepare for writing an RO1. [unreadable] [unreadable] [unreadable]